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Publication
Sortilin 1 Modulates Hepatic Cholesterol Lipotoxicity in Mice via Functional
Interaction with Liver Carboxylesterase 1.
Authors Li J, Wang Y, Matye DJ, Chavan H, Krishnamurthy P, Li F, Li T
Submitted By Submitted Externally on 9/29/2017
Status Published
Journal The Journal of biological chemistry
Year 2017
Date Published 1/6/2017
Volume : Pages 292 : 146 - 160
PubMed Reference 27881673
Abstract The liver plays a key role in cholesterol metabolism. Impaired hepatic
cholesterol homeostasis causes intracellular free cholesterol accumulation and
hepatocyte injury. Sortilin 1 (SORT1) is a lysosomal trafficking receptor that
was identified by genome-wide association studies (GWAS) as a novel regulator of
cholesterol metabolism in humans. Here we report that SORT1 deficiency protected
against cholesterol accumulation-induced liver injury and inflammation in mice.
Using an LC-MS/MS-based proteomics approach, we identified liver
carboxylesterase 1 (CES1) as a novel SORT1-interacting protein. Mechanistic
studies further showed that SORT1 may regulate CES1 lysosomal targeting and
degradation and that SORT1 deficiency resulted in higher liver CES1 protein
abundance. Previous studies have established an important role of hepatic CES1
in promoting intracellular cholesterol mobilization, cholesterol efflux, and
bile acid synthesis. Consistently, high cholesterol atherogenic diet-challenged
Sort1 knock-out mice showed less hepatic free cholesterol accumulation,
increased bile acid synthesis, decreased biliary cholesterol secretion, and the
absence of gallstone formation. SORT1 deficiency did not alter hepatic ceramide
and fatty acid metabolism in high cholesterol atherogenic diet-fed mice.
Finally, knockdown of liver CES1 in mice markedly increased the susceptibility
to high cholesterol diet-induced liver injury and abolished the protective
effect against cholesterol lipotoxicity in Sort1 knock-out mice. In summary,
this study identified a novel SORT1-CES1 axis that regulates cholesterol-induced
liver injury, which provides novel insights that improve our current
understanding of the molecular links between SORT1 and cholesterol metabolism.
This study further suggests that therapeutic inhibition of SORT1 may be
beneficial in improving hepatic cholesterol homeostasis in metabolic and
inflammatory liver diseases.




Strains




Genes
SymbolDescription
Sort1sortilin 1

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